Join our online Q&A on exon skipping

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  • #128505
    Join our online Q&A on exon skipping

    Hi everyone,

    This Tuesday 10th May, 6pm to 7pm, we’ll be joined on Talk MD by Professor Francesco Muntoni from Great Ormond Street Hospital and Sarepta Therapeutics for an online Q&A on exon skipping.

    We hope you’ll be able to join us to put your questions. However, if you won’t be able to follow the discussion on Tuesday please put any burning questions below and we’ll make sure they’re answered!

    Thanks,

    Peter

    Senior Policy and Campaigns Officer at MDUK

    Muscular Dystrophy UK staff member

    Alexa Follen
    Moderator
    Posts: 32
    Joined: 12/05/2015
    #128563
    Reply To: Join our online Q&A on exon skipping

    I recently attended the FDA Adcomm in the US.
    Here are some reflections of that panel meeting and questions that I would like to put to Francesco and Sarepta:

    FDA Adcomm Eteplirsen Washington April 2016

    Overall I thought that there was sufficient evidence to show that eteplirsen was having a clinical benefit to patients with no or insignificant risk. However the FDA’s critical analysis raised some important questions for clinicians, researchers, biotech companies and the Duchenne community.

    Biomarker evidence to FDA

    There is evidence from RT-PCR that exon 51 mRNA with eteplirsen supports its mechanism. “But evidence does not show how much mRNA was produced or whether this mRNA led to production of dystrophin” Eric Bastings FDA

    The proportion of muscle fibres with dystrophin by immunoflourescence was 17% +- 10%. Eric Bastings FDA: “It is not clear whether 17% constitutes an increase from baseline. Also immunoflourescence is mainly used for showing location rather than quantifying dystrophin.”

    By western blot, the best quantitive measure, shows 0.9% +-0.8% dystrophin. Eric Bastings FDA questions how much this is over baseline.

    FDA comment that there is no clear data to suggest a threshold when the level of dystrophin might have clinical benefit.

    Muscle biopsies are an invasive method and require anaesthesia. This restricts the number of biopsies that can be taken and raises questions about the ethical need for an operation requiring anaesthetics. Exon skipping by this method does not produce an even distribution of protein. There is a chance that samples might be from muscle cells not well skipped or conversely an unrepresentative high level of protein.

    Q Will clinical trials with eteplirsen still use dystrophin as a a primary outcome?

    If so what methods can be employed to improve the measure of dystrophin protein and what would the target threshold be to show clinical benefit?

    Clinical Evidence

    No significant difference between boys treated with eteplirsen and placebo as measured by the 6mwt for study201 over 24 weeks – the only randomized study.

    No significant difference between boys treated with eteplirsen and placebo as measured by the 6mwt for study202 over 48 weeks.

    However, highly significant results for 6mwt 162m when compared to external controls for study 201/202.

    Only two boys lost ambulation as compared to 10 out 13 in controls over 4 years.

    There was agreement that 162 meters would show effect but FDA questioned if he difference might be related to other factors e.g. steroid use, physical interventions, lack of randomisation, matches between study and patient registry populations. FDA are concerned with bias introduced before, during and after the trial. The FDA also suggested that methods of collecting data using 6mwt and NSAA might be influenced by caregivers and even the boys themselves.

    Q Why are measures against placebo not showing an effect even after 48 weeks?

    What is the agreed ethical time limit for continuing the use of placebos in Duchenne trials?

    How will trial design recognise the need for small sample size in a rare disease like Duchenne?

    How will trial design recognise that Duchenne patients now take a range of drugs and use physical management interventions that could also influence clinical outcomes?

    How will future trials be conducted to ensure that bias is not unnecessarily introduced in measuring clinical outcomes?

    Are the 6MWT and NSAA valid and reliable measures of clinical benefit?

    6MWT and the NSAA are measures that do not include quality of life measures for non ambulant patients. How will future trials include non ambulant patients and what outcome measures could be included?

    Patient and parent advocacy

    Without doubt the evidence presented by young men and family members from real life scenarios (eg climbing in and out of a car) was very compelling and this backed up the overall evidence from Sarepta that there was some measure of clinical benefit following the use of eteplirsen. This evidence, however, was also open to accusations of bias and subjectivity.

    Q How can patients and family members be involved in future trials so that the evidence that they can offer be quantified by reliable and valid measures?

    NickCatlin
    Participant
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    Joined: 09/05/2016
    #128599
    Reply To: Join our online Q&A on exon skipping

    Hello! I’m inquiring about the 45 trials. My son has been on the list at Cincinnati Children’s for a few months but the clinical trial coordinator there hasn’t heard any news on it yet. It was supposed to have already started recruiting. If the FDA doesn’t approve 51 will they still move forward with 45/53? He is also eligible for the utrophin trial which is supposed to get started in the next month. What are your thoughts about it? I don’t want to miss my chance on utrophin holding off for 45 to start if it’s not going to happen. Thank you.

    Missy0622
    Participant
    Posts: 0
    Joined: 09/05/2016
    #128619
    Reply To: Join our online Q&A on exon skipping

    Hello,

    My son William was recently diagnosed with Duchenne Muscular Dystrophy. William has exon deletion 45-52. I am looking into all research which could possibly help with his condition. I am aware this is focused on exon 51. Could you inform me whether this treatment is something that could help William’s deletion in future or does he have too many exons deleted?

    Many thanks,
    Caroline Calvert

    williamdmd
    Participant
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    Joined: 10/05/2016
    #128647
    Reply To: Join our online Q&A on exon skipping

    The FDA cited in the briefing document for Eteplirsen that “The lack of an effect with the higher dose group tends to undermine the finding in the lower dose group”. Is it possible that the lack of effect in the higher dose range could be attributed to an increased activation of endogenous miRNA pathways leading to post-transcriptional gene silencing? Is Sarepta currently investigating methods to mitigate RNAi pathways that may lead to an adjuvant therapy to increase exon skipping effectiveness?

    Shouldn’t preliminary evidence indicating any increase (even 0.9%) in dystrophin be considered “substantial” over current therapies and therefore meet the threshold for breakthrough therapy designation under FDASIA?

    KOMDTC
    Participant
    Posts: 0
    Joined: 10/05/2016
    #128650
    Reply To: Join our online Q&A on exon skipping

    Hi!
    We are from Croatia. Our son, Lovre is 2y,2m old, and he was diagnosed with Ullrich CMD when he was 1.5 years old. He has a dominant de nuovo mutation on COL6 A3 gene, skipping exon 16, and imunohistochemical painting has showed decreased collagen 6 in skin fibroblasts. We know that dr. Bonneman from NIH, Bethesda works on preclinical trials with exon skipping on COL6A3 (dermal skin cells). What sort of clinical trials are there in Europe in this moment, and do you think that Lovre would be a good candidate for clinical trials for exon skipping, becuse of his mutation?

    Greetings from Croatia!

    Ivana Bilic
    Participant
    Posts: 0
    Joined: 10/05/2016
    #128654
    Reply To: Join our online Q&A on exon skipping

    Good evening from Francesco Muntoni

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
    Participant
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    Joined: 05/05/2016
    #128655
    Reply To: Join our online Q&A on exon skipping

    Hi everyone,
    Welcome to our online Q&A on exon skipping with Professor Francesco Muntoni from Great Ormond Street Hospital and Dr Ed Kaye, Celeste DiJohnson and Dana Martin of Sarepta Therapeutics.
    We’re also joined by Dr Jenny Sharpe, Research Officer at Muscular Dystrophy UK.
    The chat is part of our Duchenne Dialogue series on potential treatments for Duchenne muscular dystrophy.
    The format is simple: please post your questions on exon skipping on the thread below and we’ll be here between 6pm to 7pm (UK time) to respond.
    Thanks for taking part!

    Muscular Dystrophy UK staff member

    Alexa Follen
    Moderator
    Posts: 32
    Joined: 12/05/2015
    #128657
    Reply To: Join our online Q&A on exon skipping

    I will wait for Sarepta to have the first stab at the questions on biomarkers and dystrophin and so on from Nick Catlin (and happy to comment as weel afterwards).
    Regarding the child on the list at Cincinnati Children’s . Once again Sarepta in the bext position to discuss when exon 45 will start in USA

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
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    Joined: 05/05/2016
    #128658
    Reply To: Join our online Q&A on exon skipping

    Regarding the message from Ms Calvert. This deletion is one that would respond to exon 53 exon skipping. There should be a Sarepta study starting to recruit soon, in addition to our SKIP NMD trial (on exon 53 skipping) in which however recruitment is over and we are now in the maintenance phase of 24 boys.
    I am also aware that Biomarin has a study on skipping exon 53 and you should discuss with your phisician what is realistically available to you where you live.

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
    Participant
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    Joined: 05/05/2016
    #128659
    Reply To: Join our online Q&A on exon skipping

    My name is Ravi, aged 26 and living with DMD.

    I know that nearly all clinical trials are focused on children with DMD and I understand why (including financial reasons), but what trials in relation to exon skipping are available now and in the pipeline for the forgotten people, adults with DMD?

    Also, not related to exon skipping, but is any pharmaceutical companies looking into trials in relation to the respiratory and cardiomyopathy issues that many adults with DMD suffer from?

    Ravi Mehta
    Participant
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    Joined: 10/03/2015
    #128660
    Reply To: Join our online Q&A on exon skipping

    Thanks so much for the doing this Q&A session! I am Leslie Guzmán, the mother of Diego Ramirez with Duchenne, he´s 11 years old and he’s walking. He has deletion 48-52, so he needs Exon 53. My question is – my husband is getting transferred with P&G to Europe. We can pick from Switzerland or UK. Could he join the trial under way that you are running?

    Leslie

    Twinless
    Participant
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    Joined: 10/05/2016
    #128661
    Reply To: Join our online Q&A on exon skipping

    As for the question on the FDA briefing document for Eteplirsen that “The lack of an effect with the higher dose group tends to undermine the finding in the lower dose group”.
    It is not very plausible that higher level of PMO induce higher levels of miRNA and postrtranscriptional silencing. If thsi was the case the longer duration treatment would have still led to a difference which however was not visible anymore at the later time point, suggesting that (as in animal models) duration of treatment is crucial. The short time frame is simply too short and the chance of not detecting a drug effect is high.

    As for the presence of dystrophin; the discussion on whether the quantity present was “sufficient” is academically interesting but in reality- as also highligted by Dr Woodcock from FDA, we simply have no idea from dystrophin replacement therapies on how much is sufficient to start making a difference in the human after therapy as there are no precedents. Natrual history studies and preclinical studies clearly indicate there is not a threshold for clinical efficacy, so one would be hopeful that some dystrophin is better than no dystrophin.

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
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    #128662
    Reply To: Join our online Q&A on exon skipping

    I agree with Ravi about needing trials for the forgotten DMD adults. My question is would it be financially viable for Sarepta to trial exon skipping in adults??

    UncannyVivek
    Participant
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    Joined: 01/02/2015
    #128663
    Reply To: Join our online Q&A on exon skipping

    We were waiting for feedback on trial design during FDA Advisory Committee. Since no suggestions were made on the protocol at that time, we will be actively recruiting patients into the 45/53 (ESSENCE) Trial in the near future.

    Dr Ed Kaye, CEO, Sarepta Therapeutics

    Dr Ed Kaye
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    #128664
    Reply To: Join our online Q&A on exon skipping

    We’ve had a question for Sarepta from Claire O’Hanlon in Northern Ireland whose son, Luke has Duchenne muscular dystrophy.

    Claire would like to know when Sarepta plans to submit an application to the European Medicines Agency for a licence for eteplirsen?

    Muscular Dystrophy UK staff member

    Alexa Follen
    Moderator
    Posts: 32
    Joined: 12/05/2015
    #128665
    Reply To: Join our online Q&A on exon skipping

    As for the child with Ullrich from Croatia. Dr Bonnemann at NIH has a active program of experimental studies in skin fibroblasts from UCMD children to induce silecinging of the mutant allele. We have a similar program, funded by MDUK, also in UCMD. These studies are at the moment only in cells from children, cultured in the lab. It is very premature to consider a clinical trial in children with UCMD at this point in time.

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
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    #128666
    Reply To: Join our online Q&A on exon skipping

    There are many factors that determine trial design. The most important of which are clinical endpoints that might be expected to respond to drug therapy (eg, performance of upper limb function and respiratory function). We currently conducting a trial in non/poorly-ambulant older boys with eteplirsen in the US. We are planning to look at this population in future studies with our future exon-skipping drugs.

    Dr Ed Kaye, CEO, Sarepta Therapeutics

    Dr Ed Kaye
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    Joined: 05/05/2016
    #128667
    Reply To: Join our online Q&A on exon skipping

    Regarding Ravi, aged 26 and living with DMD.
    There are plans fro non ambulant trials in DMD looking specifically at a drug (idebenone) that was shown in a recent study to help and protect respiratory muscle function decline.
    As for antisense, there have been some limited studies in the past in non ambulant individuals. At the moment however most of the focus is to have a better understainding of the best way to use these drugs and how potent they are, and to establish this in adults is very complicated (not that to do this in children is simple either, but at least the outcome measures are betetr studied, and the residual muscle mass , which is necessary for the antisense to work) better preserved.

    Professor Francesco Muntoni, Director, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital

    Professor Francesco Muntoni
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    #128668
    Reply To: Join our online Q&A on exon skipping

    Our goal is to submit an MAA for eteplirsen by the end of the year.

    Dr Ed Kaye, CEO, Sarepta Therapeutics

    Dr Ed Kaye
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    Joined: 05/05/2016
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